The present invention relates to compounds which bind to the xcex12-adrenoceptor. More particularly, the present invention relates to certain imidazo pyridines/quinolines which are xcex12 receptor modulators.
xcex12-adrenoceptor modulators are useful to treat a variety of conditions, including, hypertension, glaucoma, sexual dysfunction, depression, attention deficit hyperactivity disorder, Parkinsonism, the need for anesthesia, cardiac arrythmia and the need for analgesia. Particularly, xcex12-adrenoceptor agonists are well known analgesics. xcex12-adrenoceptor antagonists have potential as antidepressants in their own right or as adjunct therapies to traditional inhibitors of monoamine reuptake.
Clonidine is a centrally acting xcex12-adrenoceptor agonist with wide clinical utility as an antihypertensive agent. Clonidine is believed to act by inhibiting the release of norepinephrine from sympathetic nerve terminals via a negative feedback mechanism involving xcex12-adrenoceptors located on the presynaptic nerve terminal. This action is believed to occur in both the central (CNS) and peripheral (PNS) nervous systems. More recently, the role of xcex12-adrenoceptor agonists as analgesic agents in humans and antinociceptive agents in animals has been demonstrated. Clonidine and other xcex12-adrenoceptor agonists have been shown to produce analgesia through a non-opiate mechanism and, thus, without opiate liability. However, other behavioral and physiological effects were also produced, including sedation and cardiovascular effects. 
Medetomidine, detomidine, and dexmedetomidine are xcex12-adrenoceptor agonists. Dexmedetomidine is used clinically in veterinary medicine as a sedatives/hypnotic for pre-anaesthesia. These compounds are hypotensive in animals and in humans, but the magnitude of this cardiovascular effect is relatively insignificant. 
U.S. Pat. No. 3,574,844, Gardocki et al., teach 4-[4(or 5)-imidazolylmethyl]-oxazoles as effective analgesics. The disclosed compounds are of the general formula: 
Compounds of this type are insufficiently active and suffer from unwanted side effects.
U.S. Pat. No. 4,913,207, Nagel et al., teach arylthiazolylimidazoles as effective analgesics. The disclosed compounds are of the general formula: 
Compounds of this type are insufficiently active and suffer from unwanted side effects.
WO92/14453, Campbell et al., teach 4-[(aryl or heteroaryl)methyl]-imidazoles as effective analgesics. The disclosed compounds are of the general formula: 
The disclosed compounds are insufficiently: active and suffer from unwanted side effects.
Kokai No. 1-242571, Kihara et al., disclose a method to produce imidazole derivatives for use, among other uses, as antihypertensive agents. 
A single mixture of compounds meeting the above formula was reportedly produced by the inventive method. This was a mixture of 4-(2-thienyl)-methylimidazole and 4-(3-thienyl)-methylimidazole represented by the following formula: 
The disclosed compounds are insufficiently active and suffer from unwanted side effects.
U.S. Pat. No. 5,621,113 and U.S. Pat No. 5,750,720, Boyd and Rasmussen disclose certain substituted 2- and 3-thienyl methylimidazoles as effective analgesic agents. 
Many potent and selective xcex12 antagonists, such as idazoxan, have been synthesized and evaluated in limited clinical trials as antidepressants.(J. Med. Chem. 1995, 38 (23), 4615.) Mirtazapine is a closely related analog of the established antidepressant mianserin. This compound has been shown to be an antagonist at xcex12 receptors and exhibits antidepressant activity in vivo. (Exp. Opin. Invest. Drugs 1995, 4(10), 945). An agent with the dual profile of a 5 HT reuptake inhibitor and an xcex12 antagonist might serve to enhance synaptic concentrations of 5-HT relative to that achievable through 5-HT uptake inhibition alone and in turn produce a more effective antidepressant response. A novel series of compounds with such a profile was found to possess putative antidepressant effects in vivo (J. Med. Chem. 1997, 40 (7), 1049; Bioorg. Med. Chem Lett. 1995, 5, 2287.; Drug. Dev. Res. 1995, 35, 237.; Drug. Dev. Res. 1995, 35, 246.)
Briefly, there is provided by the present invention compounds which are xcex12-adrenoceptor modulators of the formula: 
where
n is 0, 1, 2;
X is independently selected from the group consisting of C1-4alkyl, bromine, chlorine, iodide, trifluoromethyl, C1-4alkoxy, xe2x80x94SO2NH2, nitro, and two adjacent X may be fused to form the moiety: 
xe2x80x83whereby a saturated, partially unsaturated or aromatic six-membered fused ring is formed;
Y is independently selected from the group consisting of hydrogen, hydroxy, C1-4alkyl, C1-4alkoxy, trifluoromethyl and phenyl; and
Z is independently selected from the group consisting of hydroxy, C1-4alkyl, bromine, chlorine, iodide, trifluoromethyl, C1-4alkoxy, xe2x80x94SO2NH2 and nitro.
The compounds of the present invention are prepared by the methods shown in Schemes 1 to 5. In Scheme 1, heterocyclic carboxylic acid 1 is converted to its Weinreb amide 2 by published procedures (Weinreb and Nahm, Tetrahedron Letters, 1981, 22, 3815) which is then reacted with the Grignard reagent derived from N1-trityl-4-iodoimidazole (Turner and Lindell, J. Org. Chem. 1991, 56, 5739) to give the ketone intermediate 3. This ketone intermediate 3 could be deoxygenated by reaction with a reagent such as HI to give product 4. Alternatively, as depicted in Scheme 2, the intermediate ketone 3 could be reacted with an alkyl or aryllmagnesium halide (or other Grignard or lithium reagent) to give 5 which is then deoxygenated and deprotected to yield 6. Suitable means of deoxygenation/deprotection include 57% hydriodic acid, hydrogenation using Pd(OH)2 as catalyst, triethylsilane/trifluoroacetic acid, borane/methylsulfide or NaBH4/trifluoroacetic acid. 
In Scheme 3, heterocyclic aldehyde 7 reacts with the Grignard reagent derived from N1-trityl-4-iodoimidazole (Turner and Lindell, J. Org. Chem. 1991, 56, 5739) to yield the heterocyclic hydroxymethylimidazole intermediate 8. This intermediate is deoxygenated and deprotected in one step for example with refluxing HI or another suitable means such as described above to give product 9.
In the case where X is hydrogen, C1-4alkyl, C1-4alkoxy and trifluoromethyl, the appropriately substituted heterocyclic hydroxyimidazoles 5 or 8 may be produced and the substituent in question will stably endure the reactions of Scheme 2 and Scheme 3 to arrive at target products 6 and 9 respectively. In the case where X is chlorine, bromine, and nitro, the above described deoxygenation-deprotection steps could also be achieved using triethylsilane/trifluoroacetic acid, 57% hydriodic acid or other means such as borane/methylsulfide or NaBH4/trifluoroacetic acid. 
In Scheme 4, heterocyclic carbinol 10 is converted to the bromide by reaction with a brominating agent such as CBr4/PPh3 or PBr3. The bromide 11 reacts with PPh3 to yield the triphenylphosphonium reagent 12 which undergoes Wittig reaction with N1-tritylimidazole-4-carboxaldehyde in the presence of a suitable base such as NaOMe/MeOH or LiHMDS. The requisite N1-tritylimidazole-4-carboxaldehyde is easily obtained by published procedures (Jetter et al, Org. Prep. Proc. Intl. 1996, 28, 709.). The products of the Wittig reaction 13 are deprotected with an acid such as hydrochloric acid, formic acid or trifluoroacetic acid and then reduced by hydrogenation with an appropriate catalyst to yield the target 14. 
In Scheme 5, hydroxyquinoline 15 is converted to its triflate by reaction with a strong base such as NaH and an appropriate triflating agent such as N-phenyl trifluoromethanesulfonimide to give quinolyl triflate 16. The triflate 16 could be condensed in a Stille coupling reaction with a 4-(stannyl)imidazole reagent in the presence of Pd(0) to give 17, or condensed with the 4-imidazo Grignard reagent described above in the presence of ZnCl2 to also give 17. The tritylated intermediate 17 is then deprotected with acid (HCl, trifluoracetic acid or formic acid) to give the target product 18. Scheme 5 depicts quinoline as the substrate but the same sequence of reactions could be performed on an isoquinoline substrate. 
Where the term C1-4alkyl is employed, there are included methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl. In the case of the term C1-4alkoxy, there are included the equivalent xe2x80x94O(C1-4alkyl).
Preferred compounds of the present invention are: 
where X, Y, Z and n are dependently selected from the group consisting of:
The compounds of the present invention may be used to treat a medical condition as named herein, such as, mild to moderate pain in warm-blooded animals, such as, humans by administration of an effective dose. The dosage range would be from about 10 to 3000 mg, in particular about 25 to 1000 mg or about 100 to 500 mg, of active ingredient 1 to 4 times per day for an average (70 kg) human although it is apparent that activity of individual compounds of the invention will vary as will the pain being treated. In regard to the use of these xcex12-adrenoceptor modulators to treat hypertension, glaucoma, sexual dysfunction, depression, attention deficit hyperactivity disorder, the need for anesthesia and cardiac arrythmia, a therapeutically effective dose can be determined by persons skilled in the art by use of established animal models. Pharmaceutical compositions of the invention comprise the formula (I) compounds as defined above, particularly in admixture with a pharmaceutically-acceptable carrier.
To prepare the pharmaceutical compositions of this invention, one or more compounds of the invention or salt thereof as the active ingredient, is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, though other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above.
The pharmaceutically acceptable salts referred to above generally take a form in which the imidazolyl ring is protonated with an inorganic or organic acid. Representative organic or inorganic acids include hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benezenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic or saccharic.
Biological Procedures
The activity of compounds of the invention as xcex12 modulators may be demonstrated by the in vivo and in vitro assays as described below:
Alpha-2D Adrenergic Receptor Binding Assay
Male, Wistar rats (150-250 g, VAF, Charles River, Kingston, N.Y.) are sacrificed by cervical dislocation and their brains removed and placed immediately in ice cold HEPES buffered sucrose. The cortex is dissected out and homogenized in 20 volumes of HEPES sucrose in a Teflon(trademark)-glass homogenizer. The homogenate is centrifuged at 1000 g for 10 min, and the resulting supernatant centrifuged at 42,000 g for 10 min. The resulting pellet is resuspended in 30 volumes of 3 mM potassium phosphate buffer, pH 7.5, preincubated at 25xc2x0 C. for 30 min and recentrifuged. The resulting pellet is resuspended as described above and used for the receptor binding assay. Incubation is performed in test tubes containing phosphate buffer, 2.5 mM MgCl2, aliquots of the synaptic membrane fraction, the ligand 3H-para-aminoclonidine and test drug at 25xc2x0 C. for 20 min. The incubation is terminated by filtration of the tube contents through glass fiber filter sheets. Following washing of the sheets with 10 mM HEPES buffer, the adhering radioactivity is quantified by liquid scintillation spectrometry.
Binding of the test drug to the receptor is determined by comparing the amount of radiolabeled ligand bound in control tubes without drug to the amount of radiolabeled ligand bound in the presence of the drug. Dose-response data are analyzed with LIGAND, a nonlinear curve fitting program designed specifically for the analysis of ligand binding data. This assay is described by Simmons, R. M. A., and Jones, D. J., Binding of [3H-]prazosin and [3H-]p-aminoclonidine to xcex1-Adrenoceptors in Rat Spinal Cord, Brain Research 44 5:338-349, 1988.
Mouse Acetylcholine Bromide-Induced Abdominal Constriction Assay (MAIT)
The mouse acetylcholine bromide-induced abdominal constriction assay, as described by Collier et al. in Brit. J. Pharmacol. Chem. Ther., 32: 295-310, 1968, with minor modifications was used to assess analgesic potency of the compounds herein. The test drugs or appropriate vehicle were administered orally (p.o.) and 30 minutes later the animal received an intraperitoneal (i.p.) injection of 5.5 mg/kg acetylcholine bromide (Matheson, Coleman and Bell, East Rutherford, N.J.). The mice were then placed in groups of three into glass bell jars and observed for a ten minute observation period for the occurrence of an abdominal constriction response (defined as a wave of constriction and elongation passing caudally along the abdominal wall, accompanied by a twisting of the trunk and followed by extension of the hind limbs). The percent inhibition of this response to a nociceptive, stimulus (equated to % analgesia) was calculated as follows: The % Inhibition of response, i.e., % analgesia is equal to the difference between the number of control animals responding and the number of drug-treated animals responding times 100 divided by the number of control animals responding.
At least 15 animals were used for control and in each of the drug treated groups. At least three doses were used to determine each dose response curve and ED50 (that dose which would produce 50% analgesia). The ED50 values and their 95% fiducial limits were determined by a computer assisted probit analysis.
Biological Data
Table 1 lists certain biological data of the compounds made in the examples below wherein the position of attachment of the imidazole-containing side chain and variables X, Y and n are thus indicated.